"Duke Nukem 64 is a Nintendo 64 port of the first-person shooter PC (MS-DOS) video game Duke Nukem 3D. There are many changes from the PC version. For instance, some weapons use two different types of ammo and many of the original game's mature themes have been watered down.

Duke Nukem 64 also included multiplayer modes, allowing 4 deathmatch as well as 2 player co-operative play through split screen.

Duke's pistol can use dum-dum rounds, which are significantly more powerful than the standard ammunition, capable of killing the strongest adversaries in one shot. The shotgun can fire explosive rounds, with devastating results on Duke's enemies; as well as on Duke himself if the player is not careful. Heat-seeking missiles are also available. There are several new weapons as well: a grenade launcher (replacing the RPG), dual SMGs (replacing the chain-gun cannon), the Microwave Expander (from the Atomic Edition), a missile launcher (replacing the Devastator), and the Plasma Cannon (this weapon replaces the Freeze Thrower). The Cannon causes enemies to fade out of existence.

The game levels include real-life locations, such as a bank and a movie lot. There are more fantastic locations, such as a space station overrun by alien biology.

The game is no longer played in episodes, but as one big game, and also includes some levels from the Atomic Edition at various points. All in-game music has been removed, due to the limited storage available on the cartridge; the only music remaining is a remix of the original "Grabbag" theme (on the title screen) and the status screen theme. There are Overlord Clones in tandem with the Battlelord Clones. The new alien boss from the Atomic edition, the Protector Drone renamed as "Alien Beast", has been added to the game; and the Cycloid Emperor (in the final level) is now a fully rendered polygon character."